Abstract Burn-triggered rises in catecholamines and corticosteroids drive a persistent hypermetabolic, hypercatabolic state, which is partially attenuated by the ?-adrenergic receptor antagonist propranolol (Prop), now standard- of-care (SOC) at our institution. Data suggest that burn-induced androgen depletion also drives the catabolic response and have linked it to mortality and other negative outcomes. The objective of this P50 Center is to clarify how simultaneously blocking burn-triggered disengagement of androgen pathways and engagement of corticosteroid pathways with the testosterone analog oxandrolone (OX) affects the hypermetabolic and catabolic response, downstream sequelae (abnormal glucose metabolism, immune dysfunction, poor wound healing, hypertrophic scar), and overall patient recovery when superimposed on SOC measures. Given the role of androgens in sexual dimorphism, differential sex responses will be also defined. Our P50 Center will pursue three interrelated aims, which will be supported by Administrative, Human Subjects, and Biostatistics Cores. Aim 1 (Project 1 [P1]) will comprise a randomized, double-blinded study aimed at determining the extent to which corticosteroid/androgen pathway modulation improves clinical outcomes, whole-body function, and psychosocial health in severely burned adults and children by comparing OX administration with administration of placebo + SOC (including Prop). Project 1 will provide clinical correlates necessary for a full understanding of tissue-specific mechanistic data collected in Aims 2 & 3. Aim 2 (P9) will determine the basic mechanisms underlying the effects of corticosteroid/androgen pathway modulation on burn-induced changes in muscle, fat, and glucose metabolism by pairing stable isotope and kinetic studies in patients with biochemical and histological analyses of patient tissue. Aim 3 (P2, 7, 8) will determine the mechanisms underlying the effects of corticosteroid/androgen modulation on the inflammatory response and related processes of wound healing and infection resistance through pharmacologic studies in mice; studies of humanized murine chimeras; molecular, histological, and genomic studies in tissues/cells isolated from patients; and investigations of wound healing/scarring in patients. We expect that, compared to SOC, OX + SOC will more completely normalize aberrant muscle, fat, and glucose metabolism while improving wound healing, protecting against immune suppression, and providing more complete patient recovery. Such findings will form the basis for multicenter studies aimed at incorporating OX into the SOC worldwide, which would ultimately yield greater survival after burns, less morbidity, shorter hospitalizations, and better quality of life. This program is innovative because it will advance knowledge of the fundamental mechanisms by which androgen and corticosteroid pathways contribute to tissue catabolism and inflammation after severe burns. Insights from these studies are expected to open new avenues of inquiry into the pathophysiological state arising after burns, as well as other forms of severe trauma, and provide new targets for the development of more effective treatment strategies.